Cell Surface Expression of Human Ether-a-go-go-related Gene (hERG) Channels Is Regulated by Caveolin-3 Protein via the Ubiquitin Ligase Nedd4-2

The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr) which plays an important role in cardiac repolarization. A reduction or increase in hERG current can cause long or short QT syndrome, respectively, leading to fatal cardiac arrhythmia...

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Published in:	The Journal of biological chemistry 2012-09, Vol.287 (40), p.33132-33141
Main Authors:	Guo, Jun, Wang, Tingzhong, Li, Xian, Shallow, Heidi, Yang, Tonghua, Li, Wentao, Xu, Jianmin, Fridman, Michael D., Yang, Xiaolong, Zhang, Shetuan
Format:	Article
Language:	eng
Subjects:	Animals Caveolin Caveolin 3 - metabolism Cell Biology Cell Membrane - metabolism Endosomal Sorting Complexes Required for Transport - metabolism Ether-A-Go-Go Potassium Channels - metabolism Female Gene Expression Regulation Heart Ventricles - metabolism HEK293 Cells hERG Humans Immunohistochemistry - methods Male Muscle Cells - cytology Nedd4 Ubiquitin Protein Ligases Patch Clamp Patch-Clamp Techniques Point Mutation Protein Expression Rats RNA, Small Interfering - metabolism Ubiquitin Ligase Ubiquitin-Protein Ligases - metabolism
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Summary:	The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr) which plays an important role in cardiac repolarization. A reduction or increase in hERG current can cause long or short QT syndrome, respectively, leading to fatal cardiac arrhythmias. The channel density in the plasma membrane is a key determinant of the whole cell current amplitude. To gain insight into the molecular mechanisms for the regulation of hERG density at the plasma membrane, we used whole cell voltage clamp, Western blotting, and immunocytochemical methods to investigate the effects of an integral membrane protein, caveolin-3 (Cav3) on hERG expression levels. Our data demonstrate that Cav3, hERG, and ubiquitin-ligase Nedd4-2 interact with each other and form a complex. Expression of Cav3 thus enhances the hERG-Nedd4-2 interaction, leading to an increased ubiquitination and degradation of mature, plasma-membrane localized hERG channels. Disrupting Nedd4-2 interaction with hERG by mutations eliminates the effects of Cav3 on hERG channels. Knockdown of endogenous Cav3 or Nedd4-2 in cultured neonatal rat ventricular myocytes using siRNA led to an increase in native IKr. Our data demonstrate that hERG expression in the plasma membrane is regulated by Cav3 via Nedd4-2. These findings extend our understanding of the regulation of hERG channels and cardiac electrophysiology. Background: Alterations in hERG-encoded K+ channel current can cause fatal cardiac electrical disturbances. Results: Caveolin-3 enhances ubiquitin ligase Nedd4-2 interaction with mature hERG channels in the plasma membrane, leading to decreased channel expression. Conclusion: Caveolin-3 regulates hERG expression and thus function via Nedd4-2. Significance: Understanding of hERG regulation pathway is important for cardiac electrophysiology and antiarrhythmic strategies.
ISSN:	0021-9258 1083-351X